Amide derivatives

ABSTRACT

The invention provides amide derivatives which are useful as analgesics, anti-inflammatory agents, antimicrobial drugs, hypoglycemic agents, hypolipidemic agents, antihypertensive agents, anti-cancer agents, etc., the derivatives being represented by the formula ##STR1## wherein ring A represents a benzene ring, a naphthalene ring, a pyridine ring or a furan ring; R 4  represents a heterocyclic group selected from the group consisting of a lower alkyl-substituted thieno[3,2-d]pyrimidin-4-yl group, an optionally substituted pyrazolo[1,5-a]-1,3,5-triazin-4-yl group, a pyrazolo[3,4-d]pyrimidin-4-yl group substituted at the 6-position and a purin-6-yl group substituted at the 2-position; and R 5  represents a hydrogen atom or a group represented by ##STR2##

This application is a 371 of PCT/JP97/01875 filed Jun. 2, 1997.

TECHNICAL FIELD

The present invention relates to novel amide derivatives.

PRIOR ART

The derivatives of the invention are novel compounds which have not beenpublished in any literature. An object of this invention is to providecompounds useful as medicine.

DISCLOSURE OF THE INVENTION

The present invention provides novel derivatives represented by thefollowing formula (1). ##STR3##

In the formula (1), ring A represents a benzene ring, a naphthalenering, a pyridine ring or a furan ring; when ring A is other than abenzene ring, R¹, R² and R³ are all hydrogen atoms, and when ring A is abenzene ring, R¹, R² and R³ are the same or different and independentlyrepresent hydrogen, lower alkoxy, halogen, nitro, lower alkyl,halogen-substituted lower alkyl, phenyl, phenoxy, lower alkanoyloxy,hydroxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl.

Further, R⁴ represents a heterocyclic group selected from the groupconsisting of:

(1) a lower alkyl-substituted thieno[3,2-d]pyrimidin-4-yl group;

(2) a pyrazolo[1,5-a]-1,3,5-triazin-4-yl group optionally having one ortwo substituents selected from the group consisting of lower alkyl,phenyl, phenyl(lower)alkyl, phenylthiophenyl and halogen;

(3) a pyrazolo[3,4-d]pyrimidin-4-yl group which has a lower alkyl groupat the 6-position and one of whose nitrogen atoms may have aphenyl(lower)alkyl group as a substituent; and

(4) a purin-6-yl group which has a lower alkyl group at the 2-positionand one of whose nitrogen atoms may have a lower alkyl orphenyl(lower)alkyl group as a substituent.

Further, R⁵ represents a hydrogen atom or a group represented by##STR4## wherein A, R¹, R² and R³ are as defined above.

Examples of the groups in the formula (1) are shown below. As regardsthe groups, the term "lower" means C₁₋₆.

The lower alkyl group includes straight- or branched-chain lower alkylgroups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, hexyl and the like.

The lower alkoxy group includes methoxy, ethoxy, propoxy, isopropoxy,butoxy, pentyloxy, hexyloxy and the like.

The phenyl(lower)alkyl group includes benzyl, 1-phenylethyl,2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl,6-phenylhexyl and the like.

The halogen atom includes fluorine, chlorine, bromine and iodine.

The halogen-substituted lower alkyl group includes trifluoromethyl,pentafluoroethyl, heptafluoropropyl, nonafluorobutyl,undecafluoropentyl, tridecafluorohexyl and the like.

The (lower)alkanoyloxy group includes acetoxy, propionyloxy, butyryloxy,valeryloxy, hexanoyloxy, heptanoyloxy and the like.

The lower alkylthio group includes methylthio, ethylthio, propylthio,butylthio, pentylthio, hexylthio and the like.

The lower alkylsulfinyl group includes methylsulfinyl, ethylsulfinyl,propylsulfinyl, butylsulfinyl, pentylsulfinyl, hexylsulfinyl and thelike.

The lower alkylsulfonyl group includes methylsulfonyl, ethylsulfonyl,propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl and thelike.

Of the heterocyclic groups represented by R⁴, examples of (1) loweralkyl-substituted thieno[3,2-d]pyrimidin-4-yl groups are2-methylthieno[3,2-d]pyrimidin-4-yl, 2-ethylthieno[3,2-d]pyrimidin-4-yl,2-n-propylthieno[3,2-d]pyrimidin-4-yl,2-n-butylthieno[3,2-d]pyrimidin-4-yl,2-n-pentylthieno[3,2-d]pyrimidin-4-yl,2-n-hexylthieno[3,2-d]pyrimidin-4-yl and the like.

Of the heterocyclic groups represented by R⁴, examples of (2)pyrazolo[1,5-a]-1,3,5-triazin-4-yl groups optionally having one or twosubstituents selected from the group consisting of lower alkyl, phenyl,phenyl(lower)alkyl, phenylthiophenyl and halogen include unsubstitutedpyrazolo[1,5-a]-1,3,5-triazin-4-yl and the following substituted groups:

2-methylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-ethylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-n-propylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-n-butylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-n-pentylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-n-hexylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-phenylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-benzylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-(2-phenylethyl)pyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-(3-phenylpropyl)pyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-(4-phenylbutyl)pyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-(5-phenylpentyl)pyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-(6-phenylhexyl)pyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-methyl-8-phenylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-ethyl-8-phenylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,8-phenyl-2-n-propylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-n-butyl-8-phenylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-n-pentyl-8-phenylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-n-hexyl-8-phenylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-methyl-7-phenylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-ethyl-7-phenylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,7-phenyl-2-n-propylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-n-butyl-7-phenylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-n-pentyl-7-phenylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-n-hexyl-7-phenylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-methyl-8-(4-phenylthiophenyl)pyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-ethyl-8-(4-phenylthiophenyl)pyrazolo[1,5-a]-1,3,5-triazin-4-yl,8-(4-phenylthiophenyl)-2-n-propylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-n-butyl-8-(4-phenylthiophenyl)pyrazolo[1,5-a]-1,3,5-triazin-⁴ -yl,2-n-pentyl-8-(4-phenylthiophenyl)pyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-n-hexyl-8-(4-phenylthiophenyl)pyrazolo[1,5-a]-1,3,5-triazin-4-yl,8-bromo-2-methylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,8-bromo-2-ethylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,8-bromo-2-n-propylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,8-bromo-2-n-butylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,8-bromo-2-n-pentylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,8-bromo-2-n-hexylpyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-n-butyl-8-fluoropyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-n-butyl-8-chloropyrazolo[1,5-a]-1,3,5-triazin-4-yl,2-n-butyl-8-iodopyrazolo[1,5-a]-1,3,5-triazin-4-yl and the like.

Of the heterocyclic groups represented by R⁴, given below are examplesof (3) pyrazolo[3,4-d]pyrimidin-4-yl groups which have a lower alkylgroup at the 6-position and one of whose nitrogen atoms may have aphenyl(lower)alkyl group as a substituent.6-Methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl,6-ethyl-1H-pyrazolo[3,4-pyrimidin-4-yl,6-n-propyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl,6-n-butyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl,6-n-pentyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl,6-n-hexyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl,6-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl,6-ethyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl,6-n-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl,6-n-butyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl,6-n-pentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl,6-n-hexyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl,2-benzyl-6-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl,2-benzyl-6-ethyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl,2-benzyl-6-n-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl,2-benzyl-6-n-butyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl,2-benzyl-6-n-pentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl,2-benzyl-6-n-hexyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl,6-n-butyl-2-(1-phenylethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl,6-n-butyl-2-(2-phenylethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl,6-n-butyl-2-(3-phenylpropyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl,6-n-butyl-2-(4-phenylbutyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl,6-n-butyl-2-(5-phenylpentyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl,6-n-butyl-2-(6-phenylhexyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl,1-benzyl-6-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl,1-benzyl-6-ethyl-1H-pyrazolo(3,4-d]pyrimidin-4-yl,1-benzyl-6-n-propyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl,1-benzyl-6-n-butyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl,1-benzyl-6-n-pentyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl,1-benzyl-6-n-hexyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl,6-n-butyl-1-(1-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl,6-n-butyl-1-(2-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl,6-n-butyl-1-(3-phenylpropyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl,6-n-butyl-1-(4-phenylbutyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl,6-n-butyl-1-(5-phenylpentyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl,6-n-butyl-1-(6-phenylhexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl,6-n-butyl-5H-pyrazolo[3,4-d]pyrimidin-4-yl,5-benzyl-6-n-butyl-5H-pyrazolo[3,4-d]pyrimidin-4-yl and the like.

Of the heterocyclic groups represented by R⁴, given below are examplesof (4) purin-6-yl groups which have a lower alkyl group at the2-position and one of whose nitrogen atoms may have a lower alkyl orphenyl(lower)alkyl group as a substituent. 2-Methyl-9H-purin-6-yl,2-ethyl-9H-purin-6-yl, 2-n-propyl-9H-purin-6-yl,2-n-butyl-9H-purin-6-yl, 2-n-pentyl-9H-purin-6-yl,2-n-hexyl-9H-purin-6-yl, 2-methyl-7H-purin-6-yl, 2-ethyl-7H-purin-6-yl,2-n-propyl-7-H-purin-6-yl, 2-n-butyl-7H-purin-6-yl,2-n-pentyl-7H-purin-6-yl, 2-n-hexyl-7H-purin-6-yl,9-benzyl-2-methyl-9H-purin-6-yl, 9-benzyl-2-ethyl-9H-purin-6-yl,9-benzyl-2-n-propyl-9H-purin-6-yl, 9-benzyl-2-n-butyl-9H-purin-6-yl,9-benzyl-2-n-pentyl-9H-purin-6-yl, 9-benzyl-2-n-hexyl-9H-purin-6-yl,2-n-butyl-9-(1-phenylethyl)-9H-purin-6-yl,2-n-butyl-9-(2-phenylethyl)-9H-purin-6-yl,2-n-butyl-9-(3-phenylpropyl)-9H-purin-6-yl,2-n-butyl-9-(4-phenylbutyl)-9H-purin-6-yl,2-n-butyl-9-(5-phenylpentyl)-9H-purin-6-yl,2-n-butyl-9-(6-phenylhexyl)-9H-purin-6-yl, 2,9-dimethyl-9H-purin-6-yl,2-ethyl-9-methyl-9H-purin-6-yl, 9-methyl-2-n-propyl-9H-purin-6-yl,2-n-butyl-9-methyl-9H-purin-6-yl, 9-methyl-2-n-pentyl-9H-purin-6-yl,2-n-hexyl-9-methyl-9H-purin-6-yl, 7-benzyl-2-methyl-7H-purin-6-yl,7-benzyl-2-ethyl-7H-purin-6-yl, 7-benzyl-2-n-propyl-7H-purin-6-yl,7-benzyl-2-n-butyl-7H-purin-6-yl, 7-benzyl-2-n-pentyl-7H-purin-6-yl,7-benzyl-2-n-hexyl-7H-purin-6-yl,2-n-butyl-7-(1-phenylethyl)-7H-purin-6-yl,2-n-butyl-7-(2-phenylethyl)-7H-purin-6-yl,2-n-butyl-7-(3-phenylpropyl)-7H-purin-6-yl,2-n-butyl-7-(4-phenylbutyl)-7H-purin-6-yl,2-n-butyl-7-(5-phenylpentyl)-7H-purin-6-yl,2-n-butyl-7-(6-phenylhexyl)-7H-purin-6-yl, 2,7-dimethyl-7H-purin-6-yl,2-ethyl-7-methyl-7H-purin-6-yl, 7-methyl-2-n-propyl-7H-purin-6-yl,2-n-butyl-7-methyl-7H-purin-6-yl, 7-methyl-2-n-pentyl-7H-purin-6-yl,2-n-hexyl-7-methyl-7H-purin-6-yl, 1-benzyl-2-methyl-1H-purin-6-yl,1-benzyl-2-ethyl-1H-purin-6-yl, 1-benzyl-2-n-propyl-1H-purin-6-yl,1-benzyl-2-n-butyl-1H-purin-6-yl, 1-benzyl-2-n-pentyl-1H-purin-6-yl,1-benzyl-2-n-hexyl-1H-purin-6-yl,2-n-butyl-1-(1-phenylethyl)-1H-purin-6-yl,2-n-butyl-1-(2-phenylethyl)-1H-purin-6-yl,2-n-butyl-1-(3-phenylpropyl)-1H-purin-6-yl,2-n-butyl-1-(4-phenylbutyl)-1H-purin-6-yl,2-n-butyl-1-(5-phenylpentyl)-1H-purin-6-yl,2-n-butyl-1-(6-phenylhexyl)-1H-purin-6-yl, 1,2-dimethyl-1H-purin-6-yl,2-ethyl-1-methyl-1H-purin-6-yl, 1-methyl-2-n-propyl-1H-purin-6-yl,2-n-butyl-1-methyl-1H-purin-6-yl, 1-methyl-2-n-pentyl-1H-purin-6-yl,2-n-hexyl-1-methyl-1H-purin-6-yl and the like.

The amide derivatives of the invention are useful as medicine, andparticularly useful as analgesics (for relieving postoperative pain,migraine, gout, chronic pain, neuropathic pain, cancer pain, etc.),anti-inflammatory agents, antimicrobial drugs, hypoglycemic agents,hypolipidemic agents, antihypertensive agents, anti-cancer agents, etc.The derivatives of the invention are highly suitable for use asanalgesics which are characterized by being free of side effectstypically seen in conventional analgesics.

Examples of the derivatives of the invention suitable for the abovemedicinal use are those of formula (1) wherein A is a benzene ring, andparticularly those wherein A is a benzene ring and the heterocyclicgroup R⁴ is either a thieno[3,2-d]pyrimidin-4-yl group substituted by alower alkyl group at the 2-position or apyrazolo[1,5-a]-1,3,5-triazin-4-yl group substituted by a lower alkylgroup at the 2-position. Among the suitable derivatives, more preferableare those wherein R¹, R² and R³ are the same or different andindependently represent hydrogen, lower alkoxy, halogen, phenyl, loweralkanoyloxy or lower alkylthio.

Examples of particularly preferable amide derivatives of the inventionare shown below.

N-(2-n-butylpyrazolo[1,5-a]-1,3,5-triazin-4-yl)-3,4,5-trimethoxybenzamide;

N-(2-n-butylpyrazolo[1,5-a]-1,3,5-triazin-4-yl)-2,4-dichlorobenzamide;

N-(2-n-butylpyrazolo[1,5-a]-1,3,5-triazin-4-yl)-3-chlorobenzamide; and

N-(2-n-butylthieno[3,2-d]pyrimidin-4-yl)-3,4,5-trimethoxybenzamide.

The derivatives of the invention can be produced by various processes.Exemplary processes are schematically shown below. ##STR5## wherein A,R¹, R², R³, R⁴ and R⁵ are as defined above, X is a halogen atom, andR^(4a) is a heterocyclic group selected from the following groups (1),(2), (3') and (4'):

(1) a lower alkyl-substituted thieno[3,2-d]pyrimidin-4-yl group;

(2) a pyrazolo[1,5-a]-1,3,5-triazin-4-yl group optionally having one ortwo substituents selected from the group consisting of lower alkyl,phenyl, phenyl(lower)alkyl, phenylthiophenyl and halogen;

(3') a pyrazolo[3,4-d]pyrimidin-4-yl group which has a lower alkyl groupat the 6-position and one of whose nitrogen atoms may have aphenyl(lower)alkyl or a suitable protective group as a substituent; and

(4') a purin-6-yl group which has a lower alkyl group at the 2-positionand one of whose nitrogen atoms may have a lower alkyl,phenyl(lower)alkyl or a suitable protective group as a substituent.

As shown in the above Reaction Scheme-1, the compound (2) and acidhalide (3) are reacted to produce a compound (1) of the invention. Thereaction can be carried out in a suitable solvent in the presence of adeacidification agent. Examples of useful solvents are aromatic oraliphatic hydrocarbons such as benzene, toluene, xylene and petroleumether; chain or cyclic ethers such as diethyl ether, dimethoxyethane,tetrahydrofuran (THF) and 1,4-dioxane; ketones such as acetone, ethylmethyl ketone and acetophenone; and halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane. Examples of preferable deacidification agents aretertiary amines such as triethylamine, N,N-diethylaniline,N-methylmorpholine, pyridine and 4-dimethylaminopyridine.

In the above reaction, there is no limitation on the amounts of acidhalide (3) and deacidification agent relative to the compound (2).However, they are preferably used in an approximately equimolar toexcessive molar amount respectively. The reaction is carried out at 0°C. to reflux temperature and completed in about 0.5-200 hours.

When acid halide (3) is used in an approximately equimolar amount, acompound (1) wherein R⁵ is hydrogen is produced as a main product. Byincreasing the amount of acid halide or extending the reaction time, anincreased amount of the compound (1) wherein R⁵ is other than hydrogencan be produced.

As regards suitable protective groups of the heterocyclic group R^(4a)defined in (3') and (4') in Reaction Scheme-1, examples are usualprotective groups automatically deprotected by the above reaction, suchas benzyloxycarbonyl, t-butoxycarbonyl, fluorenylmethyloxycarbonyl,2,2,2-trichloroethoxycarbonyl and the like. These protective groups areusually deprotected automatically by the above reaction, and even ifsome remain protected, the groups can be easily deprotected, forexample, by hydrolysis in a solvent such as methanol or ethanol in thepresence of a catalyst such as palladium-carbon at room temperature forabout 1-30 hours, or reductive deprotection with zinc powder in water oracetic acid, or treatment with a strong acid such as hydrochloric acidor trifluoroacetic acid.

The starting compound (2) can be prepared, for example, by the followingmethod shown in Reaction Scheme-2 to Reaction Scheme-6. ##STR6## whereinR⁶ are lower alkyl, Q is lower alkyl, and Y and Z are each halogen.

In Reaction Scheme-2, 3-aminothiophene-2-carboxylate (4) is reacted withan equimolar to slightly excessive molar amount of acid halide (5) in anamine solvent such as pyridine, lutidine or triethylamine at about 0° C.to room temperature for about 1-10 hours to produce an amide (6).

The amide (6) is subjected to cyclic reaction in ammonia water at about80° C. to reflux temperature for about 10 to 50 hours to produce acompound (7).

The subsequent halogenation of the compound (7) obtained by the abovereaction is carried out in the presence of a deacidification agent suchas N,N-dimethylaniline, N,N-diethylaniline or triethylamine using ahalogenating agent such as phosphorus oxychloride or phosphorusoxybromide. Since the above-mentioned halogenating agents also functionas solvents, there is no need to use any solvents in the above reaction.The reaction can also proceed using inert solvents such as benzene,toluene, xylene or the like. In the above reaction, the amount of thedeacidification agent is preferably about 1-10 times the molar amount ofthe compound (7). The reaction is carried out at room temperature to thereflux temperature of the solvent and completed in about 5-50 hours.

The compound (8) thus obtained can be converted into a compound (2a) bytreatment with ammonia water. This reaction is carried out by heatingthe compound (8) in ammonia water at about 70° C. to reflux temperaturefor about 5 to 30 hours. ##STR7## wherein R⁶, Q and Y are as definedabove, R⁷ is phenyl(lower)alkyl or a suitable protective group andR^(7a) is phenyl(lower)alkyl.

In Reaction Scheme-3, the pyrazole derivative (9) is reacted with anequimolar to excessive molar amount of ortho-acid-ester (10) in an inertsolvent such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA)or dimethyl sulfoxide (DMSO) at approximately reflux temperature for 10minutes to 1 hour to produce a compound (11).

Subsequently the compound (11) can be converted into a compound (2b) byreaction with an excessive amount of ammonia in an inert solvent such asmethanol, ethanol or ethylene glycol. The reaction is carried out atabout 0° C. to room temperature and completed in about 10 to 50 hours.

The compound (2b) can be converted into compounds (2c) and (2d) byreaction with halide (12). The reaction is carried out in an inertsolvent such as DMF, DMA or DMSO in the presence of a base such assodium hydride, potassium hydride, sodium ethoxide, sodium carbonate ortriethylamine. In the reaction, halide (12) and a base are usedpreferably in an approximately equimolar to excessive molar amountrelative to the starting compound. The reaction is usually carried outwith ice-cooling and completed in about 0.5-10 hours.

Also, the compound (11) can be converted into a compound (2e) byreaction with an amine (13) in an inert solvent such as methanol,ethanol or ethylene glycol. Using the amine (13) in an amount of 1 to 2equivalents, the reaction is carried out at about room temperature toreflux temperature for about 1-10 hours, thus providing a compound (2e).##STR8## wherein R⁶, Q and Y are as defined above, R⁸ is lower alkyl,phenyl(lower)alkyl or a suitable protective group and R^(8a) is loweralkyl or phenyl(lower)alkyl.

The reactions shown in Reaction Scheme-4 can be carried out in a similarmanner as the corresponding reactions in Reaction Scheme-3. ##STR9##wherein R⁶, R^(7a), R^(8a) and Q are as defined above.

In Reaction Scheme-5, the compounds (16)-(19) can be converted intocompounds (20)-(23) by reaction with ortho-acid-ester (10). Thesecompounds are then treated with ammonia to produce compounds (2c'),(2d'), (2g') and (2h'). The reactions can be carried out in a similarmanner as the corresponding reactions shown in Reaction Scheme-3.##STR10## wherein Q is as defined above, R⁹ is lower alkyl or phenyl andR¹⁰ is hydrogen, lower alkyl, phenyl, phenyl(lower)alkyl orphenylthiophenyl.

The reaction of the compound (24) with ortho-acid-ester (10) in ReactionScheme-6 can be carried out in a similar manner as the correspondingreaction shown in Reaction Scheme-3.

The compound (25) obtained by the reaction is reacted with cyaminade inthe presence of an inert solvent such as methanol, ethanol or ethyleneglycol to produce a compound (2j). The reaction is carried out using 1to 1.5 equivalent of cyanamide at about room temperature to refluxtemperature and is completed in about 3 to 30 hours.

The above reaction can be carried out by a single step. For example,about 1 equivalent each of ortho-acid ester (10) and cyanamide are addedto a solution of the compound (24) in an inert solvent (e.g., methanol,ethanol or ethylene glycol) and the reaction is carried out at roomtemperature to reflux temperature for about 5 to 30 hours. ##STR11##wherein A, R¹, R², R³, R⁵ and R⁹ are as defined above, and R^(10a) is ahalogen atom.

The halogenation of the compound (1y) shown in Reaction Scheme-7 can becarried out in an inert solvent such as benzene, carbon tetrachloride,1,2-dimethoxyethane or water using a halogenating agent such asN-bromosuccinimide (NBS), N-chlorosuccinimide or bromine. Thehalogenating agent is generally used in an amount of 1 equivalent to aslightly excessive amount relative to the compound (1y). The reaction iscarried out at 0° C. to room temperature for about 15 minutes to 3hours, thus proving a compound (1z). ##STR12## wherein R¹, R² and R⁴ areas defined above, R^(3a) is lower alkanoyloxy, R^(1a) and R^(2a) are thesame or different and independently represent hydrogen, lower alkoxy,halogen, nitro, lower alkyl, halogen-substituted lower alkyl, phenyl,phenoxy, hydroxy, lower alkylthio, lower alkylsulfinyl or loweralkylsulfonyl, R^(5a) is hydrogen or a group represented by ##STR13##wherein R¹, R² and R^(3a) are as defined above, and R^(5b) is hydrogenor a group represented by ##STR14## wherein R^(1a) and R^(2a) are asdefined above.

The compound (1w) of the invention can be converted into the compound(1x) of the invention by hydrolysis. The hydrolysis can be carried outby treating the compound (1w) with aqueous NaOH solution, aqueous KOHsolution or the like in an inert solvent such as methanol or ethanol. Inthis reaction, the reaction temperature is generally selected from therange of 0° C. to room temperature and reaction time from about 10minutes to 3 hours. ##STR15## wherein R¹, R² and R⁴ are as definedabove, φ is lower alkyl, n is 1 or 2, R^(1b) and R^(2b) are the same ordifferent and independently represent hydrogen, lower alkoxy, halogen,nitro, lower alkyl, halogen-substituted lower alkyl, phenyl, phenoxy,lower alkanoyloxy, hydroxy, lower alkylthio, lower alkylsulfinyl orlower alkylsulfonyl, R^(5c) represents hydrogen or a group representedby ##STR16## wherein R^(1b), R^(2b), n and φ are as defined above, andR^(5d) is hydrogen or a group represented by ##STR17## wherein R^(1b),R^(2b), n and φ are as defined above.

The oxidation reaction of the compound (1u) can be carried out in aninert solvent such as acetic acid, dichloromethane or carbontetrachloride using an oxidizing agent such as hydrogen peroxide,m-chloroperbenzoic acid or sodium periodate. To provide loweralkylsulfinyl (n=1) by oxidation, the oxidizing agent is used in anequimolar to slightly excessive amount relative to the starting compoundand the reaction is carried out at about 0° C. to room temperature forabout 15 minutes to 10 hours. To provide lower alkylsulfonyl (n=2), theoxidation reaction is carried out at about 0° C. to reflux temperaturefor about 15 minutes to 10 hours, using the oxidizing agent in an amountof at least 2 equivalents relative to the starting compound andoptionally using a catalyst such as sodium tungstenate.

The objective compound (1v) wherein n=2 (sulfonyl compound) can also beobtained by re-oxidizing the above obtained compound wherein n=1(sulfinyl compound) under any of the two reaction conditions.

The objective compounds in the steps of the above Reaction Schemes canbe easily isolated and purified by conventional separation means, suchas adsorption chromatography, preparative thin-layer chromatography,recrystallization, solvent extraction and the like.

The compounds of the invention can be converted into pharmaceuticallyacceptable acid addition salts, which are also included in the scope ofthe invention. Examples of useful acids to form such salts arehydrochloric acid, hydrobromic acid, sulfuric acid and like inorganicacids; and oxalic acid, fumaric acid, maleic acid, tartaric acid, citricacid, p-toluenesulfonic acid and like organic acids. The reaction forforming such an acid addition salt can be carried out by a conventionalmethod.

The compounds of the invention wherein R⁵ is hydrogen can be converted,by conventional methods, to sodium salts, potassium salts or like alkalimetal salts, calcium salts, magnesium salts or like alkali earth metalsalts, other copper salts, etc. These salts are also included in thescope of the invention.

Of the compounds of the invention, the compounds (1a) and (1b) may haveresonance structures (1c)-(1e) and (1f)-(1h) shown below and thus can berepresented by any of these formulas. ##STR18##

The compounds of the invention are made into general dosage forms ofpharmaceutical compositions using suitable pharmaceutically acceptablecarriers. Examples of useful pharmaceutically acceptable carriers areconventional diluents or excipients such as fillers, volume builders,binders, humectants, disintegrators, surfactants, lubricants and thelike. Carriers for use are suitably selected according to the desiredunit dosage forms.

A suitable unit dosage form can be selected from a wide variety of formsaccording to the intended medical treatment. Typical examples aretablets, pills, powders, solutions, suspensions, emulsions, granules,capsules, suppositories, injections (solutions, suspensions, etc.),ointments and the like.

The tablets can be molded using, as pharmaceutically acceptablecarriers, excipients such as lactose, sucrose, sodium chloride, glucose,urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicicacid and potassium phosphate; binders such as water, ethanol, propanol,simple syrup, glucose syrup, starch solution, gelatin solution,carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose andpolyvinyl pyrrolidone; disintegrators such as sodium carboxymethylcellulose, calcium carboxymethyl cellulose, low-substitutedhydroxypropyl cellulose, dry starch, sodium alginate, agar powder,laminaran powder, sodium hydrogen-carbonate and calcium carbonate;surfactants such as polyoxyethylene sorbitan fatty acid esters, sodiumlauryl sulfate and stearyl monoglyceride; disintegration inhibitors suchas sucrose, stearin, cacao butter and hydrogenated oil; absorptionpromoters such as quaternary ammonium base and sodium lauryl sulfate;humectants such as glycerin and starch; adsorbents such as starch,lactose, kaolin, bentonite and colloidal silicic acid; and lubricantssuch as purified talc, stearic acid salt, boric acid powder andpolyethylene glycol.

If necessary, the tablets can further be coated with usual coating filmto make them into sugar-coated tablets, gelatin-coated tablets, enterictablets, film-coated tablets, double-layered tablets or multiple-layeredtablets.

The pills can be made using, as pharmaceutically acceptable carriers,excipients such as glucose, lactose, starch, cacao butter, hydrogenatedvegetable oil, kaolin and talc; binders such as gum arabic powder,tragacanth powder, gelatin and ethanol; and disintegrators such aslaminaran and agar.

The suppositories can be molded using, as pharmaceutically acceptablecarriers, polyethylene glycol, cacao butter, higher alcohols or theiresters, gelatin, semisynthetic glycerides and the like.

The capsules are usually manufactured in a conventional manner byblending the compound of the invention with pharmaceutically acceptablecarriers as mentioned above and encapsulating the mixture into hardgelatin capsule shells, soft capsule shells, etc.

When the compound of the invention is to be provided in an injectableform such as solution, emulsion or suspension, the preparation ispreferably sterilized and rendered isotonic with respect to the blood.As the diluent for use in such a preparation, water, ethyl alcohol,macrogols, propylene glycol, ethoxylated isostearyl alcohol,polyoxyisostearyl alcohol, polyoxyethylene sorbitan fatty acid esters,etc. can be mentioned. In this operation, a sufficient amount of sodiumchloride, glucose, glycerin or the like may be added to thepharmaceutical composition to provide an isotonic solution. Conventionalsolubilizers, buffers, anesthetics, etc. may also be added.

Further, coloring agents, preservatives, aromatics, flavors, sweetenersor other medicines may be optionally incorporated in the pharmaceuticalcomposition.

The ointments in the form of pastes, creams, gels, etc. can bemanufactured using diluents such as white vaseline, paraffin, glycerin,cellulose derivatives, polyethylene glycol, silicone and bentonite.

The proportion of the compound of the invention (as an active ingredientcompound) in the pharmaceutical composition is not critical and can beselected from a broad range. It is generally preferable that thecompound account for about 1 to 70 weight % of the final composition.

There is no limitation on methods for administering the pharmaceuticalcompositions of the invention. Thus, a proper method can be selectedaccording to the dosage form, patient's age, sex and other conditions,severity of disease, etc. For example, the tablets, pills, solutions,suspensions, emulsions, granules and capsules are administered by theoral route. The injections are administered singly or in admixture withglucose, amino acid or like conventional infusions by the intravenousroute or, if necessary, administered singly by the intramuscular,intradermal, subcutaneous or intraperitoneal route. The suppositoriesare administered intrarectally.

The dosage of the pharmaceutical composition is suitably selectedaccording to the intended use, patient's age, sex and other conditions,severity of disease, etc. The dosage of the compound of the invention asthe active ingredient is preferably about 0.5-20 mg per kg body weight aday, and this amount can be administered once or in 2-4 divided doses aday.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described below in more detail withreference to Reference Examples and Examples. Preparation examples ofthe starting compounds for the compounds of the invention are shown asReference Examples, and preparation examples of the compounds of theinventions as Examples.

REFERENCE EXAMPLE 1 Preparation of4-amino-2-n-butylthieno[3,2-d]pyrimidine

3.8 ml of n-pentanoic acid chloride was added to 50 ml of an anhydrouspyridine solution containing 5.0 g of methyl3-aminothiophene-2-carboxylate at 0° C. The mixture was stirred at 0° C.for 1 hour and further stirred at room temperature for 2 hours. Thereaction mixture was concentrated, diluted with ethyl acetate and washedwith 1N chloric acid, saturated aqueous sodium bicarbonate solution andsaturated aqueous sodium chloride solution in this order. Ethyl acetatewas distilled off under reduced pressure and the residue was purified bysilica gel column chromatography (elution with n-hexane:ethylacetate=5:1) to provide 7.0 g of methyl3-pentanoylaminothiophene-2-carboxylate as a colorless oily compound.

To 5 ml of a dimethoxyethane solution containing 4.0 g of the compoundobtained above was added 20 ml of 25% ammonia water. The mixture wassealed in a tube and heated at 100° C. for 24 hours. The reactionmixture was concentrated under reduced pressure and extracted withdichloromethane. The organic layer was collected and concentrated underreduced pressure. The crude crystals obtained were recrystallized fromdichloromethane-n-hexane to provide 1.35 g of5-n-butyl-7-hydroxythieno[3,2-d]pyrimidine as colorless crystals.

To 14 ml of a toluene solution containing 1.35 g of -the crystalsobtained were added 2.4 ml of phosphorus oxychloride and 1.3 ml oftriethylamine. The mixture was stirred at 115° C. for 12 hours. Thereaction mixture was concentrated under reduced pressure, poured intoice water and neutralized with sodium acetate and filtered throughCelite. The filtrate was extracted with ethyl acetate. The organic layerwas collected, washed with water and then with saturated aqueous sodiumchloride solution and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (elution withn-hexane:ethyl acetate=4:1) to provide 1.4 g of5-n-butyl-7-chlorothieno[3,2-d]pyrimidine as a colorless oily compound.

To 3 ml of a dimethoxyethane solution containing 1.4 g of the oilycompound obtained was added 15 ml of 25% ammonia water. The mixture wassealed in a tube and heated at 80° C. for 20 hours. After completion ofthe reaction, the reaction mixture was cooled with water. The crystalsprecipitated were collected by filtration, washed with water and thendried to provide 1.2 g of the objective compound as colorless crystals.4-Amino-2-n-propylthieno[3,2-d]pyrimidine was prepared in a similarmanner as above.

REFERENCE EXAMPLE 2 Preparation of4-amino-6-n-butyl-1H-pyrazolo[3,4-d]pyrimidine

To 50 ml of an anhydrous DMF solution containing 5 g of3-amino-4-cyanopyrazole was added 12 ml of trimethyl ortho-n-pentanoate.The mixture was stirred at 90° C. for 20 minutes. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated aqueous sodium chloride solution and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (elution with n-hexane:ethyl acetate=2:1) to provide 6.5g of 4-cyano-3-[N-(1-methoxypentylidene)amino]pyrazole as a colorlessoily compound.

To 6.5 g of the compound obtained above was added 50 ml of a methanolsolution of ammonia (about 7%). The mixture was stirred at roomtemperature for 36 hours. After completion of the reaction, the reactionmixture was concentrated under reduced pressure and the residue wasrecrystallized from ethanol-n-hexane to provide 4.1 g of the objectivecompound as colorless crystals.

REFERENCE EXAMPLE 3 Preparation of4-amino-2-benzyloxycarbonyl-6-n-butyl-2H-pyrazolo[3,4-d]pyrimidine

To 7.5 ml of an anhydrous DMF solution containing 750 mg of the compoundobtained in Reference Example 2 were added 1.1 ml of triethylamine and3.4 ml of benzyloxycarbonyl chloride (about 30% toluene solution) at 0°C., followed by stirring at 0° C. for 1 hour. The reaction mixture waspoured into ice water, and the crystals precipitated were collected byfiltration and washed with diethyl ether. The crude crystals werepurified by silica gel column chromatography (elution withchloroform:methanol=40:11→10:1) and recrystallized from ethanol-n-hexaneto provide 390 mg of the objective compound as colorless crystals.

REFERENCE EXAMPLES 4 AND 5 Preparation of4-amino-2-benzyl-6-n-butyl-2H-pyrazolo[3,4-d]pyrimidine and4-amino-1-benzyl-6-n-butyl-1H-pyrazolo[3,4-d]pyrimidine

Using the compound obtained in Reference Example 2, benzyl bromide andsodium hydride as a base, the procedure was carried out in a similarmanner as in Reference Example 3. The crude product obtained wasrecrystallized from dichloromethane-diethyl ether to provide4-amino-2-benzyl-6-n-butyl-2H-pyrazolo[3,4-d]pyrimidine as colorlesscrystals.

On the other hand, the mother liquor of recrystallization wasconcentrated and the residue was purified by column chromatography(elution with n-hexane:ethyl acetate=2:3) and further recrystallizedfrom diethyl ether-n-hexane to provide4-amino-1-benzyl-6-n-butyl-1H-pyrazolo[3,4-d]pyrimidine as colorlesscrystals.

REFERENCE EXAMPLE 6 Preparation of 6-amino-2-n-butyl-9H-purine

To 24 ml of an anhydrous DMF solution containing 10 g of4-amino-5-cyanoimidazole was added 24 ml of trimethylortho-n-pentanoate. The mixture was stirred at 90° C. for 20 minutes.The reaction mixture was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (elution withethyl acetate) and recrystallized from ethyl acetate-n-hexane to provide17.7 g of 5-cyano-4-[N-(1-methoxypentylidene)amino]imidazole ascolorless crystals.

To 15 g of the compound obtained above was added 100 ml of a methanolsolution of ammonia (2N). The mixture was stirred at room temperaturefor 6 days. After completion of the reaction, the crystals precipitatedwere collected, washed with methanol and dried to provide 9.5 g of theobjective compound as colorless crystals. The filtrate was concentratedand the residue was recrystallized from ethanol-n-hexane to provide 3.0g of the objective compound as colorless crystals.

REFERENCE EXAMPLE 7 Preparation of6-amino-9-benzyloxycarbonyl-2-n-butyl-9H-purine

To 100 ml of an anhydrous DMF solution containing 10 g of the compoundobtained in Reference Example 6 were added 22 ml of triethylamine and 45ml of benzyloxycarbonyl chloride (about 30% toluene solution) at 0° C.,followed by stirring at 0° C. for 5 hours. The reaction mixture waspoured into ice water and extracted with chloroform. The chloroformlayer was washed with saturated aqueous sodium chloride solution andconcentrated under reduced pressure. The residue was recrystallized fromchloroform-diethyl ether to provide 8.5 g of the objective compound as acolorless crystals. The mother liquor was concentrated and the residuewas purified by silica gel column chromatography (elution withchloroform:methanol=20:1) and recrystallized from chloroform-diethylether to provide 2.4 g of the objective compound as colorless crystals.

REFERENCE EXAMPLE 8 Preparation of 6-amino-1-benzyl-2-n-butyl-1H-purine

5 g of 5-cyano-4-[N-(1-methoxypentylidine)amino]imidazole obtained inReference Example 6 was dissolved in 50 ml of methanol, and 3.2 ml ofbenzylamine was added. The mixture was stirred at 50° C. for 2 hours andallowed to stand for cooling. The crystals precipitated were collectedby filtration and washed with diethyl ether to provide 6.2 g of theobjective compound as colorless crystals.

REFERENCE EXAMPLE 9 Preparation of 6-amino-2-n-butyl-1-methyl-1H-purine

The procedure was carried out in a similar manner as in ReferenceExample 8 to provide the objective compound as colorless crystals.

REFERENCE EXAMPLE 10 Preparation of 6-amino-7-benzyl-2-n-butyl-7H-purine

Using 1-benzyl-4-amino-5-cyanoimidazole, the procedure was carried outin a similar manner as in Reference Example 6. The objective compoundwas obtained as colorless crystals.

REFERENCE EXAMPLE 11 Preparation of 6-amino-9-benzyl-2-n-butyl-9H-purine

Using 3-benzyl-4-amino-5-cyanoimidazole, the procedure was carried outin a similar manner as in Reference Example 6. The objective compoundwas obtained as colorless crystals.

REFERENCE EXAMPLE 12 Preparation of4-amino-2-n-butylpyrazolo[1,5-a]-1,3,5-triazine

To 250 ml of an anhydrous DMF solution of 50 g of 3-aminopyrazole wasadded 120 ml of trimethyl ortho-n-pentanoate, followed by stirring at70° C. for 22 hours. After completion of the reaction, the reactionmixture was concentrated under reduced pressure and the residue waspurified by silica gel column chromatography (elution withdichloromethane:methanol=50:1→20:1) to provide 60 g of3-[N-(1-methoxypentylidene)amino]pyrazole as a colorless oily compound.

The above obtained compound, 60 g, was dissolved in 300 ml of methanol,followed by addition of 15.3 g of cyanamide. The mixture was stirred at60° C. for 17 hours. After completion of the reaction, the reactionmixture was concentrated under reduced pressure and the residue waspurified by silica gel column chromatography (elution withdichloromethane:methanol=50:1), and further recrystallized fromdiisopropyl ether to provide 36.4 g of the objective compound ascolorless crystals. The mother liquor of recrystallization was purifiedin a similar manner as above to provide 7 g of the objective compound ascrystals.

REFERENCE EXAMPLE 13 Preparation of4-amino-2-phenylpyrazolo[1,5-a]-1,3,5-triazine

The procedure was carried out in a similar manner as in ReferenceExample 12 to provide the objective compound as colorless crystals.

REFERENCE EXAMPLES 14-20

The procedure was carried out in a similar manner as in ReferenceExample 12 to provide the following compounds as crystals.

REFERENCE EXAMPLE 14 4-Amino-2-methylpyrazolo[1,5-a]-1,3,5-triazineREFERENCE EXAMPLE 15 4-Amino-2-ethylpyrazolo[1,5-a]-1,3,5-triazineREFERENCE EXAMPLE 16 4-Amino-2-n-propylpyrazolo[1,5-a]-1,3,5-triazineREFERENCE EXAMPLE 17 4-Amino-2-n-pentylpyrazolo[1,5-a]-1,3,5-triazineREFERENCE EXAMPLE 18 4-Amino-2-benzylpyrazolo[1,5-a]-1,3,5-triazineREFERENCE EXAMPLE 194-Amino-2-n-butyl-8-phenylpyrazolo[1,5-a]-1,3,5-triazine REFERENCEEXAMPLE 204-Amino-2-n-butyl-8-(4-phenylthiophenyl)pyrazolo[1,5-a]-1,3,5-triazineEXAMPLE 1 Preparation ofN-(2-n-butylthieno[3,2-d]pyrimidin-4-yl)-3,4,5-trimethoxybenzamide

To 4 ml of an anhydrous pyridine solution containing 200 mg of thecompound obtained in Reference Example 1 was added 270 mg of3,4,5-trimethoxybenzoyl chloride at 0° C. The mixture was stirred at 0°C. for 1 hour and further stirred at room temperature for 3 days. Thereaction mixture was diluted with chloroform, washed with 10%hydrochloric acid, saturated aqueous sodium bicarbonate solution andsaturated aqueous sodium chloride solution in this order andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (elution with n-hexane:ethyl acetate=3:2), andfurther recrystallized from n-hexane to provide 160 mg of the objectivecompound as colorless crystals. Table 1 shows the structure and meltingpoint of the compound obtained.

EXAMPLES 2-8

The compounds set forth in Table 1 were prepared in a similar manner asin Example 1. Table 1 shows the structures and melting points of thecompounds obtained. As regards the oily compounds, ¹ H-NMR spectral data(δ: ppm; solvent: CDCl₃ ; inner standard: tetramethylsilane) are shown.

EXAMPLE 9 Preparation ofN-(2-n-butyl-9H-purin-6-yl)-3,4,5-trimethoxybenzamide

To 50 ml of an anhydrous pyridine solution containing 5 g of thecompound obtained in Reference Example 7 was added 5.3 g of3,4,5-trimethoxybenzoyl chloride at 0° C. The mixture was stirred at 0°C. for 2 hours and further stirred at room temperature for 5 days. Thereaction mixture was diluted with chloroform, washed with 10%hydrochloric acid and then with 5% aqueous sodium hydroxide solution.The aqueous layer was collected, neutralized with 10% hydrochloric acidand extracted with chloroform. The chloroform layer was collected,washed with water and then with saturated aqueous sodium chloridesolution and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (elution withchloroform:methanol=50:1→20:1) and recrystallized fromdichloromethanediethyl ether to provide 2.7 g of the objective compoundas colorless crystals. Table 1 shows the structure and melting point ofthe compound obtained.

EXAMPLE 10 Preparation ofN-(6-n-butyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3,4,5-trimethoxybenzamide

To 2 ml of an anhydrous pyridine solution containing 100 mg of thecompound obtained in Reference Example 3 was added 106 mg of3,4,5-trimethoxybenzoyl chloride at 0° C. The mixture was stirred at 0°C. for 1 hour and further stirred at room temperature for 1 hour. Thereaction mixture was diluted with ethyl acetate, washed with 10%hydrochloric acid, saturated aqueous sodium bicarbonate solution andsaturated aqueous sodium chloride solution in this order and thenconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (elution with chloroform:ethyl acetate=1:1)and further recrystallized from dichloromethane-n-hexane to provide 150mg of colorless crystals.

The crystals obtained were dissolved in 10 ml of ethanol, and 20 mg of10% palladium-carbon was added. In a hydrogen gas atmosphere, themixture was stirred at room temperature overnight. Palladium-carbon wasfiltered off using Celite, and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (elution with chloroform:methanol=50:1) and furtherrecrystallized from ethyl acetate-n-hexane to provide 60 mg of theobjective compound as colorless crystals. Table 1 shows the structureand melting point of the compound obtained.

EXAMPLES 11 AND 12 Preparation ofN-(9-benzyl-2-n-butyl-9H-purin-6-yl)-3,4,5-trimethoxybenzamide andN-(9-benzyl-2-n-butyl-9H-purin-6-yl)-N-(3,4,5-trimethoxybenzoyl)-3,4,5-trimethoxybenzamide

To 30 ml of an anhydrous pyridine solution containing 1.5 g of thecompound obtained in Reference Example 11 was added 1.85 g of3,4,5-trimethoxybenzoyl chloride at room temperature. The mixture wasstirred at room temperature for 6 days. The reaction mixture was dilutedwith dichloromethane, washed with 10% hydrochloric acid, saturatedaqueous sodium bicarbonate solution, water and saturated aqueous sodiumchloride solution in this order and then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(elution with dichloromethane:methanol=100: 150:1). The former fractionwas recrystallized from n-hexane to provide 0.75 g ofN-(9-benzyl-2-n-butyl-9H-purin-6-yl)-N-(3,4,5-trimethoxybenzoyl)-3,4,5-trimethoxybenzamideas colorless crystals. The latter fraction was recrystallized fromn-hexane to provide 0.72 g ofN-(9-benzyl-2-n-butyl-9H-purin-6-yl)-3,4,5-trimethoxybenzamide ascolorless crystals. Table 1 shows the structures and melting points ofthe compounds obtained.

                                      TABLE 1                                     __________________________________________________________________________      #STR19##                                                                       - Me = Methyl group, n-Bu = n-Butyl group, Ph = Phenyl group                                                              Melting Point                    Example R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 (° C.)               __________________________________________________________________________      1 3-OMe 4-OMe 5-OMe                                                                                                          H 9520##                                                                    -97                               - 2 3-OMe 4-OMe 5-OMe                                                                                                       H 185-187                       - 3 3-OMe 4-OMe 5-OMe                                                                                                       H Oil  .sup.1 H-NMR                                                           - 4 3-OMe 4-OMe 5-OMe                                                         H 159-161                       - 5 3-OMe 4-OMe 5-OMe                                                                                                       H 217-219  Hydrochloride        - 6 3-OMe 4-OMe 5-OMe                                                                                                       H 46-48                         - 7 3-OMe 4-OMe 5-OMe                                                                                                       H 124-126                       - 8 3-OMe 4-OMe 5-OMe                                                                                                       H 174-176                       - 9 3-OMe 4-OMe 5-OMe                                                                                                       H 132-134                       - 10 3-OMe 4-OMe 5-OMe                                                                                                      H 151-153                       - 11  3-OMe 4-OMe 5-OMe                                                                                                     H 92-94                         - 12  3-OMe 4-OMe 5-OMe                                                                                                     #STR31##                                                                      112-114#                     __________________________________________________________________________

¹ H-NMR data on the compound of Example 3 shown in Table 1 are presentedbelow.

0.90 (3H, t, J=7.2), 1.3-1.5 (2H, m),

1.8-1.9 (2H, m), 2.87 (2H, t, J=7.7),

3.62 (6H, s), 3.86 (3H, s), 5.6-6.2 (2H, brs),

7.18 (2H, d, J=6.9), 7.2-7.4 (5H, m),

8.13 (1H, s), 12.3-12.5 (1H, brs).

EXAMPLES 13-53

The compounds set forth in Table 2 were prepared in a similar manner asin Example 1. Table 2 shows the structures and melting points of thecompounds obtained. As regards the oily compounds, ¹ H-NMR spectral data(5: ppm; solvent: DMSO-d₆ ; inner standard: tetramethylsilane) areshown.

EXAMPLE 54 Preparation ofN-(2-n-butylpyrazolo[1,5-a]-1,3,5-triazin-4-yl)-2-methylsulfinylbenzamide

To 18 ml of an acetic acid solution containing 1.2 g of the compoundobtained in Example 47 was added 0.44 ml of 30% aqueous hydrogenperoxide solution. The mixture was stirred at room temperature for 4hours. After completion of the reaction, the reaction mixture wasneutralized with 10% aqueous sodium hydroxide solution and extractedwith dichloromethane. The organic layer was collected, washed with waterand then with saturated aqueous sodium chloride solution andconcentrated under reduced pressure. Diethyl ether was added to theresidue and the crystals precipitated were collected by filtration. Thecrude crystals were recrystallized from dichloromethane-diethyl ether toprovide 0.48 g of the objective compound as colorless crystals. Table 2shows the structure and melting point of the compound obtained.

EXAMPLE 55 Preparation ofN-(2-n-butylpyrazolo[1,5-a]-1,3,5-triazin-4-yl)-2-methylsulfonylbenzamide

To 10 ml of a chloroform solution containing 1.0 g of the compoundobtained in Example 54 was added dropwise 15 ml of a chloroform solutioncontaining 1.44 g of methachloroperbenzoate at -78° C. The mixture wasstirred at -78° C. for 45 minutes and further stirred at 0° C. for 1hour. The reaction mixture was diluted with dichloromethane, washed withaqueous sodium bicarbonate solution and then with saturated aqueoussodium chloride solution and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (elution;chloroform→chloroform:methanol=40:1) and recrystallized from ethylacetate-n-hexane to provide 0.95 g of the objective compound ascolorless crystals. Table 2 shows the structure and melting point of thecompound obtained.

EXAMPLE 56 Preparation ofN-(2-n-butylpyrazolo[1,5-a]-1,3,5-triazin-4-yl)-2-hydroxybenzamide

To 15 ml of an ethanol suspension containing 1.5 g of the compoundobtained in Example 44 was added 2.0 ml of 10% aqueous sodium hydroxidesolution at 0° C. The mixture was stirred at 0° C. for 1 hour. To thereaction mixture were added 2.2 ml of 10% hydrochloric acid and 80 ml ofwater. The crystals precipitated were collected by filtration, washedwith water and recrystallized from 60% ethanol hydrate to provide 1.12 gof the objective compound as colorless crystals. Table 2 shows thestructure and melting point of the compound obtained.

EXAMPLE 57 Preparation ofN-(2-n-butylpyrazolo[1,5-a]-1,3,5-triazin-4-yl)-4-hydroxybenzamide

Using the compound obtained in Example 46, the objective compound wasprepared in a similar manner as in Example 56. Table 2 shows thestructure and melting point of the compound obtained.

EXAMPLE 58 Preparation ofN-(8-bromo-2-n-butylpyrazolo[1,5-a]-1,3,5-triazin-4-yl)-3,4,5-trimethoxybenzamide

1.0 g of the compound obtained in Example 7 was dissolved in 20 ml of1,2-dimethoxyethane-water (3:1). After addition of 0.51 g of NBS at 0°C., the mixture was stirred at 0° C. for 1 hour. The reaction mixturewas diluted with water and the crystals precipitated were collected byfiltration. The crude crystals obtained were washed with water andrecrystallized from methanol- water to provide 0.94 g of the objectivecompound as colorless crystals. Table 2 shows the structure and meltingpoint of the compound obtained.

EXAMPLES 59-62

The compounds shown as Examples 59-62 in Table 2 were isolated from theformer fractions of silica gel column chromatography in Examples 7, 13,14 and 25 respectively. Table 2 shows the structures and melting pointsof the compounds obtained.

                                      TABLE 2                                     __________________________________________________________________________      #STR33##                                                                       - Me = Methyl group, Et = Ethyl group, n-Pr = n-Propyl group, n-Bu =       n-Butyl group,                                                                  t-Bu = t-Butyl group, n-Pe = n-Pentyl group, Ac = Acetyl group, Ph =        Phenyl group                                                                     -                                                                            Example                                                                                                                              RSTR34##                                                                    .sup.1 R.sup.2                                                                R.sup.3 R.sup.4                                                               R.sup.5 Melting                                                               point   (°                                                             C.)                    __________________________________________________________________________      13                                                                                                                                   2-CF35##                                                                    .sub.3 H H                                                                      H >112  (decompos                                                           ition)  Na salt                                                                 - 14                                                                          2-Cl H H                                                                      H >63  (decomposi                                                           tion)  Na salt                                                                  - 15                                                                          2-Cl 4-Cl H                                                                   H 100-102                                                                     - 16                                                                          2-OMe H H                                                                     H 119-121                                                                     - 17                                                                          3-Cl H H                                                                      H 116-118                                                                     - 18                                                                          4-Cl H H                                                                      H 74-76                 - 19                                                                                                                                3-F H H                                                                       H 96-98                 - 20                                                                                                                                H H H ##                                                                      H 82-84                 - 21                                                                                                                                3-OMe H H                                                                     H 75-77                 - 22                                                                                                                                4-OMe H H                                                                     H 91-93                 - 23                                                                                                                                2-Cl 5-Cl H                                                                   H >134  (decompos                                                           ition)  Hydrochlori                                                           de                        - 24                                                                                                                                2-Br H H                                                                      H >135  (decompos                                                           ition)  Hydrochlori                                                           de                        - 25                                                                                                                                2-NO.sub.2 H H                                                                H 89-91                 - 26                                                                                                                                3-OMe 4-OMe                                                                 5-OMe                                                                           H 165-167                                                                     - 27                                                                          3-OMe 4-OMe                                                                 5-OMe                                                                           H 148-150                                                                     - 28                                                                          3-OMe 4-OMe                                                                 5-OMe                                                                           H 145-147                                                                     - 29                                                                          4-t-Bu H H                                                                    H 96-98                 - 30                                                                                                                                H H H ##                                                                      H 100-102                                                                     - 31                                                                          4-CF.sub.3 H H                                                                H 90-92                 - 32                                                                                                                                2-OMe 4-OMe H                                                                 H 136-138                                                                     - 33                                                                          2-OMe 3-OMe                                                                 4-OMe                                                                           H 142-144                                                                     - 34                                                                          4-Ph H H                                                                      H 119-121                                                                     - 35                                                                          2-OPh H H                                                                     H 147-149                                                                     - 36                                                                          4-O-n-Bu H H                                                                  H 116-118                                                                     - 37                                                                          3-OMe 4-OMe                                                                 5-OMe                                                                           H 213-215                                                                     - 38                                                                          H H H ##                                                                      H 76-78                 - 39                                                                                                                                H H H ##                                                                      H 100-102                                                                     - 40                                                                          3-OMe 4-OMe                                                                 5-OMe                                                                           H 115-117                                                                     - 41                                                                          3-OMe 4-OMe                                                                 5-OMe                                                                           H 164-166                                                                     - 42                                                                          3-OMe 4-OMe                                                                 5-OMe                                                                           H 150-152                                                                     - 43                                                                          2-Me H H                                                                      H Oil  .sup.1                                                               H-NMR                     - 44                                                                                                                                2-OAc H H                                                                     H 123-125                                                                     - 45                                                                          3-Cl 4-Cl H                                                                   H 113-115                                                                     - 46                                                                          4-OAc H H                                                                     H 140-142                                                                     - 47                                                                          2-SMe H H                                                                     H 111-113                                                                     - 48                                                                          2-OEt H H                                                                     H 153-155                                                                     - 49                                                                          3-OMe 4-OMe H                                                                 H 113-115                                                                     - 50                                                                          2-OMe 3-OMe H                                                                 H 147-149                                                                     - 51                                                                          3-OMe 4-OMe                                                                 5-OMe                                                                           H 172-174                                                                     - 52                                                                          3-OMe 4-OMe                                                                 5-OMe                                                                           H 150-152                                                                     - 53                                                                          3-Me H H                                                                      H 76-78 #               - 54                                                                                                                                2-SOMe H H                                                                    H 168-170                                                                     - 55                                                                          2-SO.sub.2 Me H                                                             H                                                                               H 105-107                                                                     - 56                                                                          2-OH H H                                                                      H 125-127                                                                     - 57                                                                          4-OH H H                                                                      H 169-171                                                                     - 58                                                                          3-OMe 4-OMe                                                                 5-OMe                                                                           H 160-162                                                                     - 59                                                                          3-OMe 4-OMe                                                                 5-OMe                                                                           #STR128##                                                                     93-95 9##               - 60                                                                                                                                2-CF.sub.3 H H                                                                #STR131##                                                                     128-130 #               - 61                                                                                                                                2-Cl H H                                                                      #STR134##                                                                     90-92 5##               - 62                                                                                                                                2-NO.sub.2 H H                                                                #STR137##                                                                     146-148##            __________________________________________________________________________

¹ H-NMR data on the compound of Example 43 shown in Table 2 arepresented below.

0.88 (3H, t, J=7.4), 1.2-1.4 (2H, m),

1.5-1.7 (2H, m), 2.47 (3H, s), 2.66 (2H, t,

J=6.9), 6.55 (1H, d, J=2.0), 7.2-7.4 (2H, m),

7.43 (1H, t, J=7.4), 7.62 (1H, d, J=6.9),

8.21 (1H, d, J=2.0), 11.6-11.9 (1H, brs).

EXAMPLES 63-75

The compounds set forth in Table 3 were prepared in a similar manner asin Example 1. Table 3 shows the structures and melting points of thecompounds obtained.

EXAMPLES 76-82

The compounds shown as Examples 76-82 in Table 3 were isolated from theformer fractions of silica gel chromatography in Examples 63-64 and68-72 respectively. Table 3 shows the structures and melting points ofthe compounds obtained.

EXAMPLE 83

Using the compound obtained in Example 75, the compound shown in Table 3was prepared in a similar manner as in Example 56. Table 3 shows thestructure and melting point of the compound obtained.

EXAMPLES 84-120

The following compounds can be prepared by subjecting suitable startingmaterials to similar reactions as in Reference Examples or Examples.

EXAMPLE 84 N-(2-n-butylthieno[3,2-d]pyrimidin-4-yl)-1-naphthoylamideEXAMPLE 85 N-(2-n-butyl-9H-purin-6-yl)-1-naphthoylamide EXAMPLE 86N-(1-benzyl-6-n-butyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-naphthoylamideEXAMPLE 87N-(8-bromo-2-n-butylpyrazolo[1,5-a]-1,3,5-triazin-4-yl)-1-naphthoylamideEXAMPLE 88 N-(2-n-butylthieno[3,2-d]pyrimidin-4-yl)nicotinamide EXAMPLE89 N-(2-n-butyl-9H-purin-6-yl)nicotinamide EXAMPLE 90N-(1-benzyl-6-n-butyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)nicotinamideEXAMPLE 91N-(8-bromo-2-n-butylpyrazolo[1,5-a]-1,3,5-triazin-4-yl)nicotinamideEXAMPLE 92 N-(2-n-butylthieno[3,2-d]pyrimidin-4-yl)-2-furancarboxyamideEXAMPLE 93 N-(2-n-butyl-9H-purin-6-yl)-2-furancarboxyamide EXAMPLE 94N-(1-benzyl-6-n-butyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-furancarboxyamideEXAMPLE 95N-(8-bromo-2-n-butylpyrazolo[1,5-a]-1,3,5-triazin-4-yl)-2-furancarboxyamideEXAMPLE 96N-(1-benzyl-6-n-butyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-chlorobenzamideEXAMPLE 97N-(2-benzyl-6-n-butyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-chlorobenzamideEXAMPLE 98 N-(9-benzyl-2-n-butyl-9H-purin-6-yl)-3-chlorobenzamideEXAMPLE 99 N-(7-benzyl-2-n-butyl-7H-purin-6-yl)-3-chlorobenzamideEXAMPLE 100N-(1-benzyl-6-n-butyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-methoxybenzamideEXAMPLE 101N-(2-benzyl-6-n-butyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-methoxybenzamideEXAMPLE 102 N-(9-benzyl-2-n-butyl-9H-purin-6-yl)-2-methoxybenzamideEXAMPLE 103 N-(7-benzyl-2-n-butyl-7H-purin-6-yl)-2-methoxybenzamideEXAMPLE 104N-(2-n-butyl-7-phenylpyrazolo[1,5-a]-1,3,5-triazin-4-yl)-3-chlorobenzamideEXAMPLE 105N-(2-n-butyl-7-phenylpyrazolo[1,5-a]-1,3,5-triazin-4-yl)-2-methoxybenzamideEXAMPLE 106N-(2-n-butyl-8-phenylpyrazolo[1,5-a]-1,3,5-triazin-4-yl)-3-chlorobenzamideEXAMPLE 107N-(2-n-butyl-8-phenylpyrazolo[1,5-a]-1,3,5-triazin-4-yl)-2-methoxybenzamideEXAMPLE 108N-[2-n-butyl-8-(4-phenylthiophenyl)pyrazolo[1,5-a]-1,3,5-triazin-4-yl]-3-chlorobenzamideEXAMPLE 109N-[2-n-butyl-8-(4-phenylthiophenyl)pyrazolo[1,5-a]-1,3,5-triazin-4-yl]-2-methoxybenzamideEXAMPLE 110 N-(9-benzyl-2-n-butyl-9H-purin-6-yl)-1-naphthoylamideEXAMPLE 111 N-(9-benzyl-2-n-butyl-9H-purin-6-yl)nicotinamide EXAMPLE 112N-(9-benzyl-2-n-butyl-9H-purin-6-yl)-2-furancarboxyamide EXAMPLE 113N-(7-benzyl-2-n-butyl-7H-purin-6-yl)-1-naphthoylamide EXAMPLE 114N-(7-benzyl-2-n-butyl-7H-purin-6-yl)nicotinamide EXAMPLE 115N-(7-benzyl-2-n-butyl-7H-purin-6-yl)-2-furancarboxyamide EXAMPLE 116N-(2-benzyl-6-n-butyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1-naphthoylamideEXAMPLE 117N-(2-benzyl-6-n-butyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)nicotinamideEXAMPLE 118N-(2-benzyl-6-n-butyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-furancarboxyamideEXAMPLE 119N-(8-bromo-2-n-butylpyrazolo[1,5-a]-1,3,5-triazin-4-yl)-3-chlorobenzamideEXAMPLE 120N-(8-bromo-2-n-butylpyrazolo[1,5-a]-1,3,5-triazin-4-yl)-2-methoxybenzamide

                                      TABLE 3                                     __________________________________________________________________________      #STR139##                                                                      - Me = Methyl group, Et = Ethyl group, n-Pr = n-Propyl group, n-Bu =       n-Butyl group,                                                                  t-Bu = t-Butyl group, n-Pe = n-Pentyl group, Ac = Acetyl group, Ph =        Phenyl group                                                                     -                                                                            Example                                                                                                                               RSTR140##                                                                   .sup.1 R.sup.2                                                                R.sup.3 R.sup.4                                                               R.sup.5 Melting                                                               point  (°                                                              C.)                   __________________________________________________________________________      63                                                                                                                                    H H H 1##                                                                     H 97142##                                                                   -99                      - 64                                                                                                                                 2-Cl H H                                                                      H  99-101                                                                     - 65                                                                          2-OMe H H                                                                     H 122-124                                                                     - 66                                                                          3-OMe 4-OMe                                                                 5-OMe                                                                           H 86-88                                                                     #         - 67                                                                  2-Cl 4-Cl H                                                                   H 139-141                                                                     - 68                                                                          3-Cl H 5-OMe                                                                  H 74-76                                                                     #         - 69                                                                  4-Cl H H                                                                      H 129-131                                                                     - 70                                                                          3-OMe H H                                                                     H 117-119                                                                     - 71                                                                          4-OMe H H                                                                     H 100-102                                                                     - 72                                                                          2-CF.sub.3 H H                                                                H 155-157                                                                     - 73                                                                          2-OMe 3-OMe                                                                 4-OMe                                                                           H 100-102                                                                     - 74                                                                          2-SMe H H                                                                     H 123-125                                                                     - 75                                                                          2-OAc 3-OMe H                                                                 H 114-117                                                                     - 76                                                                          H H H 7##                                                                     #STR168##                                                                     155-157                                                                     #         - 77                                                                  2-Cl H H                                                                      #STR171##                                                                     111-113                                                                     #         - 78                                                                  3-Cl H H                                                                      #STR174##                                                                     142-144                                                                     #         - 79                                                                  4-Cl H H                                                                      #STR177##                                                                     186-188                                                                     #         - 80                                                                  3-OMe H H                                                                     #STR180##                                                                     134-136                                                                     #         - 81                                                                  4-OMe H H                                                                     #STR183##                                                                     140-142                                                                     #         - 82                                                                  2-CF.sub.3 H H                                                                #STR186##                                                                     133-135                                                                     #         - 83                                                                  2-OH 3-OMe H                                                                  H 163-165           __________________________________________________________________________

Pharmacological Test Example 1

Using 6-week-old male S.D. rats (n=7/group), the pain threshold of eachrat's left hind paw was determined using Analgesy-Meter (product ofUnicom) in accordance with the Randall-Sellitto method [Randall, L. O.and Sellitto, J. J., Arch. Int. Pharmacodyn., 111, 409 (1957)]. Thevalue thus obtained was termed "pre-value".

One hour after measurement of the pre-value, a 5% gum arabic suspensioncontaining the active ingredient compound of the invention was orallyadministered to the rats of the test group in an amount of 10 ml/kg sothat the dosage of the active ingredient compound of the invention was10 mg/kg, whereas a 5% gum arabic suspension (not containing the activeingredient compound of the invention) was orally administered to therats of the control group in an amount of 10 ml/kg. One hour later, anaqueous physiological saline solution containing substance P (25 ng/0.1ml) was subcutaneously injected into the left hind paw of each rat.

The pain threshold of each rat's left hind paw was determined in thesame manner as above at a predetermined interval from the time of thesubstance P injection. The value thus obtained was termed "post-value".

The recovery (%) of the pain threshold was calculated from post-valuesand pre-values of the rats in each group, by means of the followingformula. ##EQU1##

The results (the highest recovery %) are shown in Table 4.

                  TABLE 4                                                         ______________________________________                                                     Recovery Time from substance P                                     Example No. (%) injection (minutes later)                                   ______________________________________                                         1           69.2     60                                                         7 39.3 15                                                                    14 54.1 60                                                                    15 83.2 30                                                                    16 47.9 30                                                                    17 74.7 60                                                                    21 34.4 60                                                                    33 57.7 60                                                                    34 41.8 30                                                                    44 56.8 60                                                                    47 50.0 30                                                                    48 68.5 30                                                                    59* 30.5 60                                                                   61 35.9 60                                                                    64 63.7 30                                                                    66 31.3 30                                                                    70 30.4 30                                                                  ______________________________________                                         *: administration amount = 1 mg/kg                                       

Table 4 clearly shows that the compounds of the invention have highanalgesic activity.

Formulation Example 1

Manufacture of Tablets

Tablets (1000 tables) for oral administration, each containing as anactive ingredient 5 mg of the compound obtained in Example 1, weremanufactured according to the following formula:

    ______________________________________                                        Compound of the invention obtained in Example 1                                                          5      g                                             Lactose (Japanese pharmacopoeia: JP) 50 g                                     Corn starch (JP) 25 g                                                         Crystalline cellulose (JP) 25 g                                               Methyl cellulose (JP) 1.5 g                                                   Magnesium stearate (JP) 1 g                                                 ______________________________________                                    

More specifically, the compound of the invention obtained in Example 1,lactose, corn starch and calcium carboxymethyl cellulose were fullyblended and granulated using an aqueous methyl cellulose solution. Thegranulated mixture was passed through a 24-mesh sieve, and the granulesunder the sieve were mixed with magnesium stearate andcompression-molded into the objective tablets.

Formulation Example 2

Manufacture of Capsules

Two-piece hard gelatin capsules (1000 units) for oral administration,each containing as an active ingredient 10 mg of the compound obtainedin Example 7, were manufactured according to the following formula:

    ______________________________________                                        Compound of the invention obtained in Example 7                                                          10     g                                             Lactose (JP) 80 g                                                             Corn starch (JP) 30 g                                                         Talc (JP) 5 g                                                                 Magnesium stearate (JP) 1 g                                                 ______________________________________                                    

More specifically, the above ingredients were finely pulverized andblended to give a homogeneous composition. This composition was filledinto proper- sized capsule shells for oral administration to provide theobjective encapsulated composition.

INDUSTRIAL APPLICABILITY

The amide derivatives of the present invention have highly potentanalgesic effects and are useful as analgesics in the field of medicine.

What is claimed is:
 1. An amide compound represented by the formula,##STR190## wherein ring A represents a benzene ring or a naphthalenering; when ring A is a naphthalene ring, R¹, R² and R³ are all hydrogenatoms, and when ring A is a benzene ring, R¹, R² and R³ are the same ordifferent and independently represent hydrogen, lower alkoxy, halogen,nitro, lower alkyl, halogen-substituted lower alkyl, phenyl, phenoxy,lower alkanoyloxy, hydroxy, lower alkylthio, lower alkyl sulfinyl orlower alkyl sulfonyl;R⁴ represents a heterocyclic group selected fromthe group consisting of (1) a lower alkyl-substitutedthieno[3,2-d]-pyrimidin-4-yl group, (2) a pyrazolo[1,5-a]-1,3,5-triazin-4-yl group optionally having one or twosubstituents selected from the group consisting of lower alkyl, phenyl,phenyl(lower)alkyl, phenylthiophenyl and halogen, (3) apyrazolo[3,4-d]pyrimidin-4-yl group which has a lower alkyl group at the6-position and one of those nitrogen atoms may have a phenyl(lower)alkyl group as a substituent, and (4) a purin-6-yl group which has alower alkyl group at the 2-position and one of whose nitrogen atoms mayhave a lower alkyl or phenyl (lower) group as a substituent; and R⁵represents a hydrogen atom or a group represented by ##STR191## whereinA, R¹, R² and R³ are as defined above.
 2. An amide compound according toclaim 1 which is represented by the formula of claim 1 wherein ring Arepresents a benzene ring.
 3. An amide compound according to claim 2which is represented by the formula of claim 1 wherein R⁴ represents athieno[3,2-d]pyrimidin-4-yl group substituted by a lower alkyl group atthe 2-position, or a pyrazolo[1,5-a]-1,3,5-triazin-4-yl groupsubstituted by a lower alkyl group at the 2-position.
 4. An amidecompound according to claim 3 which is represented by the formula ofclaim 1 wherein R¹, R² and R³ are the same or different andindependently represent hydrogen, lower alkoxy, halogen, phenyl, loweralkanoyloxy or lower alkylthio.
 5. An amide compound according to claim4 which is selected from the group consisting ofN-(2-n-butylpyrazolo[1,5-a]-1,3,5-triazin-4-yl)-3,4,5-trimethoxybenzamide,N-(2-n-butylpyrazolo[1,5-a]-1,3,5-triazin-4-yl)-2,4-dichlorobenzamide,N-(2-n-butylpyrazolo[1,5-a]-1,3,5-triazin-4-yl)-3-chlorobenzamide andN-(2-n-butylthieno[3,2-d]pyrimidin-4-yl)-3,4,5-trimethoxybenzamide. 6.An analgesic composition which comprises an amide compound defined inclaim 1 and a pharmaceutically acceptable carrier.
 7. A method forrelieving pain, which comprises administering to a patient an effectiveamount of an amide compound defined in claim 1.